Nosocomial infections are those infections that are acquired during hospitalization of a patient or any health care-associated infection including infections acquired in institutions other than acute care facilities such as nursing homes. They are infections that are newly acquired and are identified at least forty-eight hours after admission, so that infections acquired prior to entry into a health care facility are in fact excluded from the definition of nosocomial.
The most common nosocomial infections are urinary tract infections, surgical site infections, pneumonia and primary blood stream infections caused by central vascular line infections, which later is caused by the use of indwelling central vascular catheters.
6.9% of patients admitted to French hospitals, 8 to 10% of patients admitted to hospitals in Europe, other than in France and 10% of patients admitted to hospitals in the United States are stricken with at least one nosocomial infection during their stay. This results in about 4,200 deaths in France, 50,000 deaths in Europe and 99,000 deaths in the United States per year. Moreover, patients have to postpone their hospitalization anywhere from 4 to 24 days depending on the type of nosocomial infection.
Nosocomial infections are quite costly. The direct costs of hospital-acquired infections in the United States are estimated to be about $4.5 billion dollars per year. In England the cost for one health care unit is estimated to be about 3.6 million pounds per year.
The over consumption of antibiotics and in particular the antibacterial drugs are the principle cause of nosocomial infections. The constant utilization of antibiotics, and in particularly in hospitals, creates a pressure selection that favors bacteria that are resistant to certain antibiotics and contributes to bacterial strains that are multi resistant that can be transmitted from one patient to another. This phenomenon, in some instances, prevents treatment with antibiotics that were initially used to successfully treat bacterial infections. It is also known that within the next several years many antibiotics will become ineffective to treat bacterial infections due to bacterial resistance. In addition, the pharmaceutical industry placed only a few new antibiotics on the market for the last ten years.
Cell communication in bacteria, parasites and fungus occurs in a population density dependent manner and is based on the production of and response to small pheromone-like molecules called autoinducers. This form of intercellular signalling is known as quorum sensing, which is a means to communicate between the same species that optimizes the metabolic and behavorial activity. Quorum sensing regulated genes encode not only virulence factors, but also other proteins involved in the metabolic process.
The lipophilic nature of essential oils is a major drawback for their biodisperability in a hydrophilic medium. However, membranes of microorganisms possess lipophilic sites where the essential oils are in a favourable interactional environment. Films can form on the surface of the microorganisms and act as a vector for the reduction of the capacity of the microorganisms to communicate between themselves. This by consequence reduces the microorganism's capacity to form biofilms.
Traditionally quorum sensing was thought to help microorganisms to coordinate processes such as biofilm formation that would be inefficient in single cells or to prevent too many microorganisms from colonizing in too small an area. However recently it has been discovered that quorum seeking exists in single cells which are confined in an extremely enclosed space.
Essential oils are aromatic volatile concentrated hydrophobic liquids that can be found in different parts of plants such as the seeds, the roots, the bark, the wood, leaves, shoots or peel. They are generally produced and stored in the secretory cells, the gland and resinous ducts of plants. They can be obtained from plants by various processes including by compression, distillation, extraction, absorption or by applying pressure and maceration.
Essential oils can be used in many applications such as antiparasitics, insecticides, fungicides, in medicaments and in compositions for cosmetics. Essential oils are effective as anti-bacterials due to a synergistic combined action of various components on the bacterial cell wall, cell membrane metabolism and protein synthesis.
For instance WO2009/043987 describes a composition that contains an antibiotic and at least one essential oil that are used as anti-infectious agents and especially as anti-bacterials. In vivo and in vitro applications of their effectiveness are demonstrated in this patent application for a variety of bacterial infections.
There are three types of submicroscopic vectors allowing the transport of active principles which are liposomes, nanocapsules, nanospheres and nano-emulsions.
Liposomes are microscopic vesicles, generally spherically shaped, formed from one or more lipid walls. The walls are prepared from lipid molecules, which have the tendency both to form bilayers and to minimize their surface area. The lipid molecules that make up a liposome have hydrophilic and lipophilic portions. Upon exposure to water, the lipid molecules form one or several bilayer membranes wherein the lipid ends of the molecules in each layer are directed to the center of the membrane, and the opposing polar ends form the respective inner and outer surfaces of the bilayer membrane. Thus, each side of the membrane presents a hydrophilic surface while the interior of the membrane comprises a lipophilic medium.
Nanospheres are matrix type structures consisting of solid spheres, in which the active principle is trapped or dissolved.
Nanocapsules are vesicles comprising an envelope which is generally of macromolecular nature and the active principle is likely to be contained in the core limited by the envelope in the shell or adsorbed on the envelope of the vesicles.
Nanoemulsions are dispersions of very small droplets such as oil in water or water in oil having a size in the range of 10 nm to 200 nm. They are often formulated using high energy methods such as ultrasound or high pressure homogenizations that promote a very fine fractioning of emulsionated systems. Nanoemulsions can also be obtained using low energy methods such as spontaneous emulsification or phase inversion temperature.
Liposomes have some important drawbacks in drug deliver since they have a low capacity to encapsulate lipophilic drugs, are manufactured through a process that involves organic solvents, which represent potential toxicity for human use and they are leaky and unstable in biological fluids and more generally in aqueous solutions.
Nanospheres, many of which are obtained by the process of salting out, also have such problems such as the use of large quantities of acetone and salts, a long purification process, possible incompatibility between the salt use in the process and the active principle and the use of large quantities of residual polyvinylic alcohol, which is not suitable for all types of administration.
Nanocapsules and nanoemulsions also present obstacles in their preparation since large quantities of surfactants and cosurfactants are used, which can present a potential toxicity for human use. Furthermore, their formulation can involve high energy methods that can alter the chemical and biological activity of the encapsulated active principles. When formulated with low energy methods, the related suspensions suffer from kinetic instability mainly in relation with the Ostwald ripening.
EP 1 265 698 B1 describes lipid nanocapsules that have a lipid core that is liquid or semisolid at room temperature, a method for preparing these nanocapsules and their use as a medicine.
WO2009/004214 A2 describes a process of preparing nanocapsules which has the active principle encapsulated in the interior of the capsule and which is prepared by a phase-inversion temperature method.
There is a need in the art to provide essential oils or essential oil extracts that can be used for treating infections, undesirable vegetation or weeds and/or plant pathogens and more specifically bacterial infections, parasitic infections, fungal infections, undesirable vegetation or weeds and/or plant pathogens in which the essential oils or essential oil extracts are formulated such that they are more medicinally effective or effective when used in smaller amounts. There is also a need in this art to provide a delivery systems for essential oils or essential oil extracts that produce a synergistic effect.
Yet another object of the present invention is to provide a process for reducing and/or limiting and/or retarding the virulence of pathogens by enveloping the pathogens of bacteria, parasites, fungus, undesirable vegetation or weeds and/or plant pathogens by quorum sensing.
In yet another object the present invention provides essential oils or essential oil extracts encapsulated in nanocapsules or nanoparticles wherein an outer film is mechanically formed on the nanocapsules, which is in contact with the lipophilic sites of the membranes of the pathogens of bacteria, parasites, fungus, undesirable vegetation or weeds and/or plant pathogens.
This need and other objects are achieved by the present invention as evidenced by the summary of the invention, description of the preferred embodiments and the claims.